Our pre-clinical data indicate that in specific settings activation of the acid sphingomyelinase (ASMase)/ceramide signaling pathway in tumor endothelial cells in response to radiation and certain chemotherapies synergizes with direct tumor cell damage to significantly impact overall tumor response, a concept which differs from the conventional paradigm that response to these therapies is tumor parenchymal cell autonomous. Mechanistically, ASMase activation leads within sec to min to formation of plasma membrane ceramide-rich platforms (CRPs), macrodomains that organize downstream effector signaling programs leading to endothelial apoptosis. Strong support for our concepts derives from studies of xenografts of all histologies, which when implanted in asmase-/- host mice become highly resistant to gemcitabine, paclitaxel, etoposide, and high single dose radiotherapy (SDRT). Further, we recently discovered VEGF is the principal inhibitor of endothelial ASMase, and that anti-angiogenic drugs de-repress ASMase amplifying tumor response to SDRT and select chemotherapies, but only under specific conditions. In pre-clinical models, we find that irrespective of half-life or anti-angiogenic class, these drugs enhance endothelial apoptosis and tumor response only if scheduled 1-2 h preceding chemotherapy, because ASMase can be de-repressed for only 1-2 h. Based on these data, the MSK Sarcoma Service performed a Phase II trial that showed sphingolipid-based timing of the anti-angiogenic bevacizumab as opposed to conventional timing improved tumor response of metastatic sarcoma from 38 to 93% (p=0.0024). We now seek to build upon these promising results to test the hypothesis that a short-acting anti-angiogenic is better suited for repeated cycles of chemosensitization of ASMase signaling compared to agents engineered for long-term VEGF suppression. Successful study completion will directly impact follow-up sarcoma clinical trials of sphingolipid-based anti-angiogenic chemosensitization.